What Does the ‘Best Evidence’ Say About Antidepressants?

What Does the ‘Best Evidence’ Say About Antidepressants?

Irving Kirsch, associate director of the Program in Placebo Studies at Harvard Medical School, has conducted several meta-analyses of antidepressants in comparison to placebo, concluding there’s virtually no difference in their effectiveness. According to Kirsch, “The difference is so small, it’s not of any clinical importance.”19 For example:

In a 1998 meta-analysis20 that looked at 19 double-blind studies, Kirsch and colleagues noted that:

“These data indicate that virtually all of the variation in drug effect size was due to the placebo characteristics of the studies.

The effect size for active medications that are not regarded to be antidepressants was as large as that for those classified as antidepressants, and in both cases, the inactive placebos produced improvement that was 75 percent of the effect of the active drug. These data raise the possibility that the apparent drug effect (25 percent of the drug response) is actually an active placebo effect.”

Research published in 2008 found major discrepancies between published and unpublished research makes antidepressants appear far more beneficial and effective than the sum total of the research actually reveals them to be. Of 74 FDA-registered studies, 31 percent were never published.

As noted by the authors, “According to the published literature, it appeared that 94 percent of the trials conducted were positive. By contrast, the FDA analysis showed that 51 percent were positive … Selective reporting of clinical trial results may have adverse consequences for researchers, study participants, health care professionals and patients.”

A 2010 meta-analysis21 concluded that “The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms.”
In a 2011 paper,22 Kirsch notes that six-week trials have a higher success rate than eight-week trials — 55 versus 42 percent — which suggests long-term use of antidepressants is likely ineffective.
In a 2014 paper,23 Kirsch notes that “analyses of the published data and the unpublished data that were hidden by drug companies reveals that most (if not all) of the benefits are due to the placebo effect.” In this paper, he notes that two of his earlier meta-analyses24,25 actually revealed that when both published and unpublished trials were included, the placebo response accounted for a whopping 82 percent of the beneficial response to antidepressants.

A major benefit of evaluating FDA trial data was that all of the trials used the same primary measure of depression, which made the drug-to-placebo effects very easy to identify and compare. The primary measure of depression used in these studies was the Hamilton depression scale, a 17-item scale with a possible score of 0 to 53 points.

The higher your score, the more severe your depression. Importantly, the mean difference between antidepressants and placebo was less than 2 points (1.8) on this scale. To illustrate just how insignificant of a difference this is, you can score a 6-point difference simply by changing sleep patterns without any reported change in other depressive symptoms.

Simply fidgeting less results in a 4-point decrease in your depression score, so as noted by Stegenga in his essay,26 “a drug that simply made people sleep better and fidget less could lower one’s depression score by 10 points.”

What’s more, clinical guidelines in the U.K. require antidepressants to lower depression scores by a mere 3 points, 27 and this too reveals why and how the benefits of antidepressants have been overestimated and oversold.

Most recently, a 2017 systematic review with meta-analysis and trial sequential analysis of 131 placebo-controlled studies found that “all trials were at high risk of bias and the clinical significance seems questionable. SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial effects seem to be outweighed by harmful effects.”

None of the trials, even when reporting a positive result, met the threshold for clinical significance of 3 points on the depression score.

Long-Term, Antidepressant Users Fare Much Worse

What’s more, research has shown that patients who do not take antidepressants fare better in the long term compared to those taking drugs,28 and research29 comparing exercise and drug treatment for depression suggests those not taking drugs have a lower risk of relapse. This risk is also addressed in Kirsch’s 2014 paper30 on antidepressants and the placebo effect.

The serotonin theory is as close as any theory in the history of science to having been proved wrong. Instead of curing depression, popular antidepressants may induce a biological vulnerability making people more likely to become depressed in the future,” Kirsch writes.

Known Side Effects of Antidepressants

In addition to not working better than placebo, antidepressants also come with a long list of potential side effects, which include but are not limited to:31,32

Worsening depression
Self-harm, violence and suicide
Increased risk of developing Type 2 diabetes,33 even after adjusting for risk factors such as body mass index34
Thickening of the greater carotid intima-media (the lining of the main arteries in your neck that feed blood to your brain),35 which could contribute to the risk of heart disease and stroke. This was true both for SSRIs and antidepressants that affect other brain chemicals
An increased risk of heart attack, specifically for users of tricyclic antidepressants, who have a 36 percent increased risk of heart attack36
An increased risk of dementia; as the dose increases, so does the risk for dementia37
Depletion of various nutrients, including coenzyme Q10 and vitamin B12 — in the case of tricyclic antidepressants — which are needed for proper mitochondrial function. SSRIs have been linked to iodine and folate depletion38

Depression Treatments That Actually Work

If you’re at all interested in following science-based recommendations, you’d place antidepressants at the very bottom of your list of treatment candidates. Far more effective treatments for depression include:

Exercise — A number of studies have shown exercise outperforms drug treatment. Exercise helps create new GABA-producing neurons that help induce a natural state of calm, and boosts serotonin, dopamine and norepinephrine, which helps buffer the effects of stress.

Studies have shown there is a strong correlation between improved mood and aerobic capacity, but even gentle forms of exercise can be effective. Yoga, for example, has received particular attention in a number of studies. One study found 90-minute yoga sessions three times a week reduced symptoms of major depression by at least 50 percent.39

Nutritional intervention — Keeping inflammation in check is an important part of any effective treatment plan. If you’re gluten sensitive, you will need to remove all gluten from your diet. A food sensitivity test can help ascertain this. Reducing lectins may also be a good idea.

As a general guideline, eating a whole food diet as described in my optimal nutrition plan can go a long way toward lowering your inflammation level. A cornerstone of a healthy diet is limiting sugar of all kinds, ideally to no more than 25 grams a day.

In one study,40 men consuming more than 67 grams of sugar per day were 23 percent more likely to develop anxiety or depression over the course of five years than those whose sugar consumption was less than 40 grams per day. Certain nutritional deficiencies are also notorious contributors to depression, especially:

  • Marine-based omega-3 fats — Omega-3 fats have been shown to improve major depressive disorder,41 so make sure you’re getting enough omega-3s in your diet, either from wild Alaskan salmon, sardines, herring, mackerel and anchovies, or a high-quality supplement. I recommend getting an omega-3 index test to make sure you’re getting enough. Ideally, you want your omega-3 index to be 8 percent or higher.
  • B vitamins (including B1, B2, B3, B6, B9 and B12) — Low dietary folate can raise your risk by as much as 300 percent.42,43 One of the most recent studies44,45 showing the importance of vitamin deficiencies in depression involved suicidal teens. Most turned out to be deficient in cerebral folate and all of them showed improvement after treatment with folinic acid.
  • Magnesium — Magnesium supplements led to improvements in mild-to-moderate depression in adults, with beneficial effects occurring within two weeks of treatment.46
Vitamin D — Studies have shown vitamin D deficiency can predispose you to depression and that depression can respond favorably to optimizing your vitamin D stores, ideally by getting sensible sun exposure.47,48 In one study,49 people with a vitamin D level below 20 nanograms per milliliter (ng/mL) had an 85 percent increased risk of depression compared to those with a level greater than 30 ng/mL.

A double-blind randomized trial50 published in 2008 concluded that supplementing with high doses of vitamin D “seems to ameliorate [depression] symptoms indicating a possible causal relationship.”Recent research51 also claims that low vitamin D levels appear to be associated with suicide attempts. For optimal health, make sure your vitamin D level is between 60 and 80 ng/mL year-round. Ideally, get a vitamin D test at least twice a year to monitor your level.

Light therapy — Light therapy alone and placebo were both more effective than Prozac for the treatment of moderate to severe depression in an eight-weeklong study.52 Spending time outdoors in broad daylight is the least expensive and likely most effective option.
Probiotics — Keeping your gut microbiome healthy also has a significant effect on your moods, emotions and brain. You can read more in my previous article, “Mental Health May Depend on the Health of Your Gut Flora.”
Emotional Freedom Techniques (EFT) — EFT is a form of psychological acupressure that has been shown to be quite effective for depression and anxiety.53,54,55,56 For serious or complex issues, seek out a qualified health care professional who is trained in EFT to guide you through the process.

That said, for most of you with depression symptoms, this is a technique you can learn to do effectively on your own. In the video below, EFT practitioner Julie Schiffman shows you how.

Other Helpful Treatment Strategies

Here are several additional strategies that can help improve your mental health:57

Minimize electromagnetic field (EMF) exposure — In 2016, Martin Pall, Ph.D., published a review58 in the Journal of Neuroanatomy showing how microwave radiation from cellphones, Wi-Fi routers and computers and tablets not in airplane mode is clearly associated with many neuropsychiatric disorders.

These electromagnetic fields (EMFs) increase intracellular calcium and trigger the production of extremely damaging free radicals by acting on your voltage gated calcium channels (VGCCs), and the tissue with the highest density of VGCCs is your brain. Once these VGCCs are stimulated they also cause the release of neurotransmitters and neuroendocrine hormones, which contribute not only to anxiety and depression but also neurodegenerative diseases like Alzheimer’s.

So, if you struggle with anxiety or depression, be sure to limit your exposure to wireless technology. Simple measures include turning your Wi-Fi off at night, not carrying your cellphone on your body unless it’s in airplane mode, and not keeping portable phones, cellphones and other electric devices in your bedroom.

Clean up your sleep hygiene — Make sure you’re getting enough high quality sleep, as sleep is essential for optimal mood and mental health. The inability to fall asleep and stay asleep can be due to elevated cortisol levels, so if you have trouble sleeping, you may want to get your saliva cortisol level tested with an Adrenal Stress Index test.

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